Nonmelanoma skin cancer (NMSC) is more common in the United States than all other types of cancer combined. A recent study of US national databases has shown a 4.2% yearly average increase in the number of NMSC procedures in the Medicare population from 1992 to 2006, and a total of 3.5 million NMSC procedures performed in 2.2 million Medicare and non-Medicare patients in 2006 (Rogers H W et al. Arch Dermatol 146(3); 283, 2010). Assuming an unchanged rate of increase, five million NMSC procedures per year will be performed by 2015 in the US. NMSC most commonly occurs in people over the age of 50 years, however studies in the US and Europe have shown a disproportionate increased incidence in women under 40 (Christenson L J et al. JAMA 294; 681, 2005, Birch-Johansen et al. Int J Cancer Apr. 19, 2010), raising concerns of an even higher number of patients in future, and resultant increased morbidity and economic burden.
NMSC includes both squamous cell carcinoma (SCC) and basal cell carcinoma (BCC), and is caused by ultraviolet (UV)-induced mutations in epidermal cells. Seventy-five to eighty percent of new cases of NMSC each year are BCC (Tierney E P, Hanke C W. J Drugs Dermatol 8; 914-922, 2009). A recent study has shown that BCC arise from keratinocytes of the interfollicular epidermis (Youssef K K et al. Nat Cell Biol 12; 299-305, 2010). BCC appear as different histologic subtypes, including nodular (45.9% of all BCC), superficial (25.9%), infiltrative (16.0%), and micronodular (9.1%), as well as other and mixed subtypes (Raasch B A et al. Br J Dermatol 155; 401-7, 2006) Infiltrative and micronodular BCC are classified as “high risk” tumors, as are nodular tumors of the midface or ear, and large or recurrent tumors. Risk in the context of BCC refers to aggressiveness or likelihood of spread or recurrence after treatment, rather than mortality. BCC of any type or location has a very low probability of metastasis; however it is locally destructive, and if left untreated or treated incompletely may become deeply and/or widely invasive of surrounding skin and subcutaneous tissue. With the exception of superficial BCC (sBCC), which are most common on the trunk or extremities, the majority of BCC occur on the face. BCC and other NMSC have their highest incidence in people of European ethnicity, but also occur in Asian populations, and with increasing incidence (Kim H S et al. J Korean Med Sci 25; 924-9, 2010).
The first goal in treatment of BCC, as in any cancer treatment, is the complete eradication of tumor cells; the second objective is sparing surrounding normal tissue required for good cosmesis and function. Surgery and destructive methods such as cryosurgery, and electrodessication and curettage (EDC), are the mainstays for treatment of NMSC, and with those methods complete tumor cell eradication necessitates damage to normal tissue.
Of all BCC surgeries, Mohs micrographic surgery is the most tissue-sparing. It is also the most reliably effective in removing all malignant cells associated with the lesion, and has a 5 year recurrence rate of only 1% for primary tumors (Muller F M et al. Dermatol Surg 35; 1349-1354, 2009). The cost of Mohs surgery depends on the number of stages or levels that are subjected to histological analysis for mapping of the tumor and the complexity of the repair needed for the resulting skin defect. Average costs of Mohs surgery for treatment of BCC on the cheek are $1263 (Rogers H W, Coldiron B M. J Am Acad Dermatol 61; 96-103, 2009). Larger, deeper lesions or lesions in difficult anatomic locations can cost substantially more. The surgical wound can be extensive and often requires reconstruction using flaps or full thickness skin grafts. The number of physicians receiving formal training in Mohs surgery has increased substantially in the past decade, and 25% of all dermatologists now perform this procedure (Tierney E P et al. Derm Surg 35; 413-9, 2009).
Traditional surgical excision with immediate or delayed repair of the surgical defect is another standard treatment of BCC. Typically, a 4 mm margin of normal-appearing skin is excised with the tumor. A comparison of surgical excision with Mohs has shown that excision leaves a 60% larger surgical defect (Muller F M, et al. Dermatol Surg 35; 1349-1354, 2009). Remarkably, retrospective analysis has shown that 14% of BCC are incompletely excised (Malik V, et al. J Plast Reconstr Surg Aesth Surg, 2010). Because of the difficulty in determining the subsurface spread and depth of the tumor and the competing need to preserve healthy, uninvolved skin tissue, surgical excision has higher recurrence rates than Mohs surgery. The 5 year recurrence rate for primary BCC following surgical excision is approximately 5% (Thissen M R et al. Arch Dermatol 135; 177-183, 1999). Excision of a BCC on the cheek with permanent margins and immediate or delayed repair is estimated to cost on average $1006 and $1170, respectively (Rogers H W, Coldiron B M. J Am Acad Dermatol 61; 96-103, 2009).
The least costly methods of treating BCC are cryosurgery and EDC. Cryosurgery is commonly used to treat superficial BCC on the trunk or extremities. Because it is nonselectively destructive, significant scarring, skin texture changes, and hypopigmentation commonly result. As with EDC there is no opportunity to examine the margins of normal-appearing skin left behind after surgery, and so it is not a preferred treatment for BCC of aggressive subtypes or on locations associated with high risk of recurrence. The estimated average cost of EDC for BCC on the cheek and arm is $471 and $392, respectively. Five year recurrence rates for cryosurgery and EDC are 7.5 and 7.7%, respectively (Tierney E P, Hanke C W. J Drugs Dermatol 8; 914-922, 2009). Recurrences after cryosurgery or EDC are typically treated with Mohs surgery.
Although excision, Mohs, EDC and cryosurgery are effective in treating NMSC, there has been a long-standing interest in alternatives that would provide better cosmetic and functional results, and allow the patient to avoid invasive and destructive surgery. As early as the 1960's, a number of chemotherapeutic and immunotherapeutic drugs were tested (Williams A C, Klein E. Cancer 25; 450-462, 1970). Topically applied chemotherapeutic drugs produced inconsistent results on BCC, with side effects including blistering, crusting, and dermatitis. Consequently, topical chemotherapeutic drugs were largely abandoned as treatment alternatives. The exception has been 5-fluorouracil (5FU, Efudex®, Valeant Pharmaceuticals International, Aliso Viejo, Calif.) which has become a widely-used, standard treatment for actinic keratoses (AKs, epidermal precursor lesions for SCC) and is approved by FDA for treatment of sBCC when conventional treatments are impractical. Histologic cure rates of 90% have been reported for sBCC treated over a period of up to 12 weeks with 5FU (Gross K et al. Derm Surg 33; 433-9, 2007). 5FU treatment of BCC other than the superficial type may result in apparent clinical cure with tumor persisting in the deeper dermis, potentially resulting in recurrence with subclinical spread (Lee S et al. Drugs 67; 915-934, 2007).
The early immune response modifiers tested showed efficacy for superficial skin tumors, and a newer drug imiquimod (Aldara®, Graceway Pharmaceuticals, Bristol, Tenn.) was introduced in the past decade (Love W E, et al. Arch Dermatol 145; 1431-1438, 2009). Therapy involves application five times a week for six weeks. Imiquimod is currently approved by FDA only for treatment of superficial BCC less than 2 cm in diameter and only on the trunk, neck, or extremities. When imiquimod has been used to treat nodular or micronodular BCC, it has been found that clearance of the tumor in the upper layers of the skin can mask residual deeper involvement and growth, which may be the result of poor exposure of the deeper tumor to the topical drug (Sukai S A, et al. Derm Surg 35; 1831, 2009).
Both imiquimod and 5FU therapies require patient adherence to lengthy treatment regimes, and both have frequent adverse effects. Based on a review of published data, it has been recommended that use of imiquimod and 5FU be limited to patients with small superficial BCC in low risk anatomic locations when more effective surgical or destructive procedures cannot be used (Love W E et al. Arch Dermatol 145; 1431-8, 2009).
Treatment of NMSC including BCC with lesional and perilesional interferon injections avoids the problem of limited depth of drug penetration implicated in 5FU and imiquimod failures when treating non-superficial tumors. However, the injected interferon has a high incidence of systemic adverse effects and administration may require many office visits over a period of several weeks. Intralesional injections of interferons or other agents are rarely used to treat NMSC.
Photodynamic therapy (PDT), which involves activation of a photosensitizing drug with light, has been studied for many years for treatment of BCC. Effective PDT requires that both drug and light fully penetrate the tumor. PDT using the topically-applied photosensitizer aminolevulinic acid or its derivatives is approved for treatment of sBCC. A recent multi-site study reported short term results in the more common nodular BCC; patients received two to four PDT sessions preceded by debridement and debulking of the tumor to facilitate penetration of the drug. Histologically verified complete response was 73% versus 27% for a placebo control group at 6 months. (Foley P, et al. Int J Dermatol 48; 1236, 2009). Pain is a significant side effect of PDT for skin cancer.
All of the above mentioned nonsurgical alternative treatments for NMSC that involve topical agents applied to the skin surface—chemotherapeutic, immunotherapeutic or photodynamic drugs—have as a major limitation the inability to reliably treat BCC other than superficial type, which comprise only about 20% of all BCC. Other drawbacks are multiple treatment visits and prolonged treatment regimes. Although the cosmetic and functional outcomes of these alternative therapies are frequently superior to those of surgical or destructive procedures, the advantage of a traditional surgical procedure that reliably removes or destroys the tumor in a single office visit is sufficient that the alternatives currently have a minor role in treatment of BCC and other NMSC.
The potential use of laser radiation to eradicate skin cancer has been of long-standing interest, with first reports appearing only a few years after the laser was invented. Near infrared (NIR) and infrared (IR) laser treatment of NMSC is based on absorption of radiation by water, the main component of soft tissue including skin and tumor tissue. The CO2 laser operates at an IR wavelength (1.06 μm) that is very strongly absorbed by water, and therefore has limited depth of penetration in soft tissue. The CO2 laser in pulsed or repetitively scanned mode can be used to vaporize superficial skin tumors layer by layer. Larger, deeper, and infiltrative tumors are not effectively eradicated and there is little advantage in treatment of even superficial lesions with this alternative destructive technique (Prstojevich S J and Nierzwicki B J, Oral Maxillofacial Surg Clin N Am 17; 147, 2005). The CO2 laser is not recommended for routine treatment of skin cancer (Hruza G J, Dermatol Clin 20; 147, 2002).
NIR Nd:YAG lasers operating at 1064 nm penetrate much deeper in soft tissue due to the weaker absorption by water at this wavelength, and have been used to coagulate rather than vaporize skin tumors. Nd:YAG laser treatment of NMSC results in delayed wound healing, scarring, and unacceptably high recurrence rates (Landthaler M, et al. Recent Res Cancer Res 130; 417, 1995). Burn-like scars are reported to be inevitable following treatment of BCC or other skin cancers with the 1064 nm Nd:YAG laser (Karrer S, et al., Am J Clin Dermatol 2; 229, 2001). When using the Nd:YAG laser both the tumor and the surrounding normal skin absorb the NIR radiation and are heated, and both of these components are typically coagulated with the objective of eradicating all tumor cells. This thermal laser technique is “blind” as there is no means of intraoperatively or postoperatively assessing tumor cell eradication, other than by tumor recurrence. Recently, Russian researchers described the use of a high power pulsed Nd:YAG laser for treatment of a large series of patients with NMSC; treatment parameters were described as causing total destruction of the tumor and coagulative necrosis of adjacent normal tissue, healing with crusting and reepithelialization, with the end result of a smooth scar at the treatment site (Moskalik K et al., Photomed Laser Surg 27; 345, 2009). A smaller study reported using a continuous wave Nd:YAG laser in up to 4 treatment sessions in 37 patients (El-Tonsy M H et al., Dermatology Online Journal 10(2); 3, 2004). Treatments involved using a thermocouple on the skin surface away from direct exposure to the laser beam to monitor surface temperature, and irradiating the tumor site with the laser to maintain a temperature of 45° C. for 1 minute. Superficial erosion and crusting were seen as normal consequences of the treatment, which resulted in permanent scarring in 11% of patients, and 3% recurrence at 3-5 years followup. Other limitations of the El-Tonsy method include the unknown temperature at the actual locations of tumor cells below the skin surface, and the lack of any means of correlating treatment time and temperature (surface or at depth) with damage to tumor cells or surrounding normal skin. Other researchers with experience with the Nd:YAG laser do not recommend its routine use for treatment of NMSC (Raulin C, Karsai S, Schmitt L, in Laser and IPL Technology in Dermatology and Aesthetic Medicine, pp 165-175, Springer, 2011).
Thus, at present, although ablative IR and thermal NIR lasers have been in the surgical armamentarium of dermatologists for many decades, they have not been successfully adapted for standard treatment of BCC and other NMSC.
Visible wavelength vascular targeting lasers have been a recent subject of evaluation for NMSC treatment (Raulin C, Karsai S, Schmitt L, in Laser and IPL Technology in Dermatology and Aesthetic Medicine, pp 165-175, Springer, 2011). The present inventor first reported the use of the 585 nm pulsed dye laser (PDL) for BCC treatment (Beutner K R, Geisse J K, Alexander J, McMillan K Lasers Surg Med Suppl 14; 22, 2002). The PDL was evaluated as a means of treating BCC by selective eradication of the blood supply on which the tumor cells depended. This study was followed by others (Allison K P, Kiernan M N, Waters R A, Clement R M, Lasers Med Sci 18; 125-6, 2003, Campolini P, Troiano M, Bonan P, Cannarozzo G, Lotti T. Dermatol Ther 21; 402-405, 2008, Shah S M, Konnikov N, Duncan L M, Tannous Z S, Lasers Surg Med 41; 417-422, 2009). These studies demonstrated the ability of PDL treatment to eradicate some BCC of different histologic types, and cosmetic results are excellent compared to the standard nonselectively destructive treatments. Several treatment sessions are typically required for successful eradication, and not all lesions respond completely. Recently Ibrahimi et al. reported the use of a 755 nm flashlamp-pumped alexandrite laser to treat basal cell carcinoma in Gorlin's syndrome. Laser-induced microvascular injury was seen at depths to the subcutaneous tissue however treatment led to hypopigmentation and scarring (Ibrahimi O A, et al. Lasers Surg Med 43; 68, 2011). A fundamental difficulty with the photothermal vascular targeting approach, using any wavelength or combination of wavelengths preferentially absorbed by blood, is that only a portion of vessels in the irradiated volume are coagulated at fluences below the threshold for damage to nonvascular structures and scar formation; therefore, tumor eradication requires multiple treatments even in smaller or superficial tumors. To address this problem, the present inventor has described an apparatus and method for using vascular targeting lasers to treat NMSC by a combined process of targeting tumor vasculature and increasing the exposure of tumor cells to topical anticancer drugs by modification of skin permeability (McMillan K, WO/2010/102099A1). Deeper, thicker and more extensive tumors are challenging due to difficulties in selective targeting of microvasculature at depth in the dermis using vascular lasers. At present, vascular-targeting lasers including PDL and alexandrite are not yet routine alternatives to surgical excision for treatment of NMSC.
For a nonsurgical treatment for NMSC to become a routine and advantageous alternative for treatment of commonly presenting tumors and not only sBBC, it should have sufficient efficacy in eradicating tumor cells at depth within the tissue that histological examination of treatment margins (as in surgical excision or Mohs surgery) is unnecessary. This significant challenge is made more difficult by the variety of different histologic subtypes of BCC having different patterns of cellular and vascular growth, and the possibility of subsurface lateral and deep extension beyond the clinically evident portion. Furthermore, skin that is the tumor environment itself varies in thickness: neck, nasal tip, and forehead skin has thickness (combined dermal and epidermal) of 0.5, 1.2, and 1.0 mm, respectively (Ha R Y, et al. Plast Reconstr Surg 115; 1769, 2005), and skin on the back, dorsal aspect of forearm, and lateral aspect of the leg has thickness 2.5, 1.1, and 1.3 mm, respectively (Tan C Y et al. Br J Dermatol 106; 657, 1982). Also, the thickness of subcutaneous adipose tissue and/or fascia underlying the dermis is highly variable with anatomic location and between patients.
At present, with the number of BCC and other NMSC requiring treatment very high and increasing, there is a pressing need for a new treatment that (1) is highly effective, (2) provides excellent cosmetic results, (3) can be rapidly and easily performed by the physician, (4) is less costly than surgical excision or Mohs surgery, and (5) is not limited to superficial, primary tumors.